Sprinkling method for preparing powder formulations

ABSTRACT

The invention relates to a new process for producing powdered preparations for inhalation wherein a substance having a smaller particle size distribution is metered continuously through a suitable feed device onto a moving bed of a powdered substance having a larger particle size distribution.

FIELD OF THE INVENTION

The invention relates to a new process for preparing powderedpreparations for inhalation.

BACKGROUND OF THE INVENTION

For treating a number of complaints, particularly respiratory diseases,it is useful to administer the active substance by inhalation. Inaddition to the administration of therapeutically active compounds inthe form of metered aerosols and inhalable solutions, the use ofinhalable powders containing active substance is of particularimportance.

With active substances which have a particularly high efficacy, onlysmall amounts of the active substance are needed per single dose toachieve the desired therapeutic effect. In such cases, the activesubstance has to be diluted with suitable excipients in order to preparethe inhalable powder. Because of the large amount of excipient, theproperties of the inhalable powder are critically influenced by thechoice of excipient.

In powder mixture technology, it is conventional to use mixing processesbased on the dilution method. All the active substance is used and thenexcipient is added in proportions of 1:1, 1:2 or 1:4 and they are mixedtogether. More excipient is then added to the resulting mixtures incomparable proportions. This procedure is usually repeated until all theexcipient has been added. The drawback of this type of procedure is thatin some cases there are problems of homogeneity. These ariseparticularly with mixtures in which the substances have a widely varyingspectrum of particle sizes. This is particularly apparent in powdermixtures in which the substance having the smaller particle sizedistribution, the active substance, makes up only a very smallproportion of the total amount of powder.

The problem of the present invention is therefore to provide a processwhich can be used to produce inhalable powders characterised by a highdegree of homogeneity in the sense of a uniformity of content.

DETAILED DESCRIPTION OF THE INVENTION

It was found that, surprisingly, the problem outlined above can besolved by means of a process in which the substance with the smallerparticle size distribution can be added to the substance with the largerparticle size distribution by a sprinkling process.

The invention therefore relates to a process for preparing powdermixtures, characterised in that the substance with the smaller particlesize distribution is metered continuously, through a suitable feeddevice, onto a moving bed of the powdered substance with the largerparticle size distribution.

Within the scope of the present invention, unless otherwise defined, thesubstance with the smaller particle size distribution, which is veryfinely ground and is present in the resulting powder formulation in avery small proportion by mass, represents the active substance. Withinthe scope of the present invention, unless otherwise defined, thesubstance with the larger particle size distribution, which is coarselyground and is present in the resulting powder formulation in a largeproportion by mass, represents the excipient.

Preferably, the invention relates to a process for preparing powdermixtures, characterised in that the substance with the smaller particlesize distribution is metered continuously, through a suitable feeddevice, onto a moving bed of the powdered substance with the largerparticle size distribution, mixing being carried out by means of aforced-action mixer.

The bed of powder may be kept in motion by means of a rotor, forexample. Depending on the construction of the apparatus, this rotor maybe an integral part of the forced-action mixer used. By a forced-actionmixer is meant a fixed container with moving mixing components.

More particularly, the present invention relates to the above processfor preparing powder mixtures which is further characterised in that themoving bed of powder is also fluidised by means of a vibrator.

Preferably, the components of the powder mixture within the scope of theprocess according to the invention are added through a suitablescreening device, preferably through a screening granulator with a meshsize of 0.1 to 2 mm, more preferably 0.3 to 1 mm, most preferably 0.3 to0.6 mm.

Optionally, when carrying out the process according to the-invention,not all the excipient or excipient mixture but only about 85 to 99%,preferably about 95-98% of the total amount of excipient is placed inthe mixing apparatus. This may prove advantageous as, after thecontinuous addition of the active substance (the substance with thesmaller particle size distribution), any active substance still adheringto the screening device can be conveyed into the mixing unit by means ofthe remainder of the excipient (1-15%, preferably 2-5% of the totalamount of excipient).

The present invention relates in particular to a process for preparinginhalable powders containing less than 5%, preferably less than 2%, mostpreferably less than 1% of active substance mixed with a physiologicallyacceptable excipient. A preferred process according to the invention isa process for preparing inhalable powders containing 0.04 to 0.8%, mostpreferably 0.08 to 0.64%, better still 0.16 to 0.4% of active substancemixed with a physiologically acceptable excipient.

The active substance used according to the invention preferably has anaverage particle size of 0.5 to 10 μm, preferably 1 to 6 μm, mostpreferably 2 to 5 μm. The excipient which may be used in the processaccording to the invention preferably has an average particle size of 10to 100 μm, preferably 15 to 80 μm, most preferably 17 to 50 μm.Particularly preferred according to the invention are processes forpreparing inhalable powders wherein the excipient has an averageparticle size of 20-30 μm.

In some cases the excipient may also consist of a mixture of coarserexcipient with an average particle size of 15 to 80 μm and finerexcipient with an average particle size of 1 to 9 μm, wherein theproportion of finer excipient in the total quantity of excipient may be1 to 20%. If the inhalable powders which may be produced using theprocess according to the invention contain a mixture of coarser andfiner excipient fractions, it is preferable according to the inventionto prepare inhalable powders wherein the coarser excipient has anaverage particle size of 17 to 50 μm, most preferably 20 to 30 μm, andthe finer excipient has an average particle size of 2 to 8 μm, mostpreferably 3 to 7 μm. By average particle size is meant here the 50%value of the volume distribution measured with a laser diffractometerusing the dry dispersion method. In the case of an excipient mixture ofcoarser and finer excipient fractions, the preferred processes accordingto the invention are those that produce inhalable powders in which theproportion of finer excipient constitutes 3 to 15%, most preferably 5 to10% of the total amount of excipient.

The percentages given within the scope of the present invention arealways percent by weight.

If the excipient used is one of the abovementioned mixtures of coarserexcipient and finer excipient, it is again expedient according to theinvention to produce the excipient mixture using the process accordingto the invention. In this case, the excipient with the smaller particlesize distribution is metered continuously, through a suitable feeddevice, onto a moving bed of the powdered excipient with the coarserparticle size distribution.

If the excipient used is one of the abovementioned mixtures of coarserexcipient and finer excipient the excipient mixture may be obtained by alayer mixing process as an alternative to the process described above.This layer mixing process is characterised in that N+m substantiallyequal portions of the excipient having a larger particle sizedistribution and N equal portions of the excipient having a smallerparticle size distribution are placed in alternate layers in a suitablemixing vessel and after they have all been added the 2N+m layers of thetwo components are mixed together using a suitable mixer, a portion ofthe excipient having the larger particle size being put in first, whileN is an integer >0, preferably >5, and m denotes 0 or 1.

Preferably, the individual fractions of excipient are added in layersthrough a suitable screening apparatus. If desired, once the mixingprocess is finished, the entire excipient mixture can be subjected toone or more additional screening processes In principle, it ispreferable according to the invention if N is at least 10 or more, morepreferably 20 or more, better still 30 or more.

The number m may represent 0 or 1. If m denotes 0 the last fractionadded to the mixing apparatus, preferably screened into it, in a layeris the last portion of the excipient with a smaller particle sizedistribution. If m represents the number 1, the last fraction added tothe mixing apparatus, preferably screened into it, in a layer is thelast portion of the excipient with a larger particle size distribution.The two excipient components are preferably added through a screeninggranulator with a mesh size of 0.1 to 2 mm, most preferably 0.3 to 1 mm,even more preferably 0.3 to 0.6 mm. Preferably the first fraction of theN+m portions of the coarser excipient is put in first and then the firstportion of the N portions of the finer excipient fraction is added tothe mixing container. The two components are added alternately byscreening them in in layers.

After the preparation of the excipient mixture, the inhalable powder isproduced from the mixture and the desired active substance using theprocess according to the invention.

Accordingly, in another aspect, the present invention relates to aprocess for preparing powder mixtures, characterised in that thesubstance with the smaller particle size distribution (the activesubstance) is metered continuously, through a suitable feed device, ontoa moving bed of an excipient mixture consisting of a previously producedmixture of an excipient fraction with a coarser particle sizedistribution and an excipient fraction with a finer particle sizedistribution.

The inhalable powders which may be obtained using the method ofpreparation according to the invention may contain, in general, anyactive substances which may reasonably be administered by inhalation fortherapeutic purposes. Preferably, the active substances used areselected, for example, from among the betamimetics, anticholinergics,corticosteroids and dopamine agonists.

Examples of betamimetics which may be used are preferably compoundsselected from among bambuterol, bitolterol, carbuterol, clenbuterol,fenoterol, formoterol, hexoprenaline, ibuterol, pirbuterol, procaterol,reproterol, salmeterol, sulphonterol, terbutaline, tulobuterol,mabuterol,4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone,1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol,5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-on,1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butylamino)ethanoland1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanol,optionally in the form of their racemates, their enantiomers, theirdiastereomers, as well as optionally their pharmacologically acceptableacid addition salts and hydrates. It is particularly preferable to use,as betamimetics, active substances of this kind selected from amongfenoterol, formoterol, salmeterol, mabuterol,1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol,optionally in the form of their racemates, their enantiomers, theirdiastereomers, as well as optionally their pharmacologically acceptableacid addition salts and hydrates. Of the betamimetics mentioned above,the compounds formoterol and salmeterol, optionally in the form of theirracemates, their enantiomers, their diastereomers, as well as optionallytheir pharmacologically acceptable acid addition salts and hydrates, areparticularly important.

The acid addition salts of the betamimetics selected from among thehydrochloride, hydrobromide, sulphate, phosphate, fumarate,methanesulphonate and xinafoate are preferred according to theinvention. In the case of salmeterol, the salts selected from among thehydrochloride, sulphate and xinafoate are particularly preferred,especially the sulphates and xinafoates. Of outstanding importanceaccording to the invention are salmeterol ×½ H₂SO₄ and salmeterolxinafoate. In the case of formoterol, the salts selected from among thehydrochloride, sulphate and fumarate are particularly preferred,especially the hydrochloride and fumarate. Of outstanding importanceaccording to the invention is formoterol fumarate.

Anticholinergics which may be used in the processes according to theinvention are preferably salts selected from among tiotropium salts,oxitropium salts and ipratropium salts, of which tiotropium andipratropium salts are particularly preferred. In the abovementionedsalts the cations tiotropium, oxitropium and ipratropium are thepharmacologically active ingredients. By the salts which may be usedwithin the scope of the present invention are meant the compounds whichcontain, in addition to tiotropium, oxitropium or ipratropium ascounter-ion (anion) chloride, bromide, iodide, sulphate,methanesulphonate or para-toluenesulphonate. Within the scope of thepresent invention, of all the salts of the abovementionedanticholinergics, the methanesulphonate, chloride, bromide and iodideare preferred, the methanesulphonate or bromide being especiallypreferred. Of outstanding importance according to the invention are theanticholinergics selected from among tiotropium bromide, oxitropiumbromide and ipratropium bromide. Tiotropium bromide is particularlypreferred. The abovementioned anticholinergics may optionally occur inthe form of their solvates or hydrates. In the case of tiotropiumbromide, for example, tiotropium bromide monohydrate is particularlyimportant according to the invention.

Within the scope of the present invention, the term corticosteroidsdenotes compounds selected from among flunisolide, beclomethasone,triamcinolone, budesonide, fluticasone, mometasone, ciclesonide,rofleponide, GW 215864, KSR 592, ST-126 and dexamethasone. The preferredcorticosteroids within the scope of the present invention are thoseselected from among flunisolide, beclomethasone, triamcinolone,budesonide, fluticasone, mometasone, ciclesonide and dexamethasone,while budesonide, fluticasone, mometasone and ciclesonide, especiallybudesonide and fluticasone, are of particular importance. The termsteroids may be used on its own, within the scope of the present patentapplication, instead of the term corticosteroids. Any reference tosteroids within the scope of the present invention also includes areference to salts or derivatives which may be formed from the steroids.Examples of possible salts or derivatives include: sodium salts,sulphobenzoates, phosphates, isonicotinates, acetates, propionates,dihydrogen phosphates, palmitates, pivalates or furoates. Thecorticosteroids may optionally also be in the form of their hydrates.

Within the scope of the present invention, the term dopamine agonistsdenotes compounds selected from among bromocriptine, cabergolin,alpha-dihydroergocryptine, lisuride, pergolide, pramipexol, roxindol,ropinirol, talipexol, tergurid and viozan. It is preferable within thescope of the present invention to use dopamine agonists selected fromamong pramipexol, talipexol and viozan, pramipexol being of particularimportance. Any reference to the abovementioned dopamine agonists alsoincludes, within the scope of the present invention, a reference to anypharmacologically acceptable acid addition salts and hydrates thereofwhich may exist. By the physiologically acceptable acid addition saltsthereof which may be formed by the abovementioned dopamine agonists aremeant, for example, pharmaceutically acceptable salts selected fromamong the salts of hydrochloric acid, hydrobromic acid, sulphuric acid,phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid,succinic acid, lactic acid, citric acid, tartaric acid and maleic acid.

The process according to the invention for preparing powder mixtures forinhalation may be used to prepare powders which contain one or more ofthe abovementioned active ingredients. If, for example, inhalablepowders are to be prepared in which the pharmaceutically activeingredients consist of two different active substances, this can beachieved using the process according to the invention, for example, byfirst continuously metering the first active substance into a moving bedof the powdered excipient or excipient mixture and then continuouslymetering in the second active substance into this powder mixture inanalogous manner. If the process according to the invention is to beused to prepare inhalable powders which contain two active ingredients,for example, preferred possible combinations of active substances mightconsist of a combination of one of the abovementioned anticholinergicswith one of the abovementioned corticosteroids or a combination of oneof the abovementioned anticholinergics with one of the abovementionedbetamimetics.

Examples of physiologically acceptable excipients which may be used toprepare the inhalable powders according to the invention include, forexample, monosaccharides (e.g. glucose or arabinose), disaccharides(e.g. lactose, saccharose, maltose), oligo- and polysaccharides (e.g.dextrane), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g.sodium chloride, calcium carbonate) or mixtures of these excipients withone another. Preferably, mono- or disaccharides are used, while the useof lactose or glucose is preferred, particularly, but not exclusively,in the form of their hydrates. For the purposes of the invention,lactose is the particularly preferred excipient, while lactosemonohydrate is most particularly preferred.

The inhalable powders which may be obtained by the preparation processaccording to the invention are characterised by an exceptional degree ofhomogeneity in terms of uniformity of content. This is in a range of<8%, preferably <6%, most preferably <4%. The inhalable powders whichmay be prepared according to the invention may possibly even have levelsof homogeneity, in the sense of single dose accuracy, of <3%, possibly<2%. Thus, in a further aspect, the present invention relates toinhalable powders as such which may be obtained by the preparationprocess according to the invention.

The inhalable powders which may be obtained by the process according tothe invention may for example be administered using inhalers which metera single dose from a reservoir by means of a measuring chamber (e.g.according to U.S. Pat. No. 4,570,630A) or by other means (e.g. accordingto DE 36 25 685 A). Preferably, however, the inhalable powders which maybe obtained according to the invention are packed into capsules (to makeso-called inhalettes), which are used in inhalers such as thosedescribed in WO 94/28958, for example. If the inhalable powder obtainedby the process according to the invention is to be packed into capsules(inhalettes) in accordance with the preferred application mentionedabove, it is advisable to fill the capsules with amounts of from 3 to 10mg, preferably from 4 to 6 mg of inhalable powder per capsule, thisamount depending to a large extent on the choice of active substanceused. In the case of the active substance tiotropium bromide, thecapsules contain between 1.2 and 80 μg of tiotropium cation, for theamounts of filling mentioned above. With a filling of 4 to 6 mg ofinhalable powder per capsule, the preferred amount for tiotropiumbromide, the content of tiotropium per capsule is between 1.6 and 48 μg,preferably between 3.2 and 38.4 μg, most preferably between 6.4 and 24μg. A content of 18 μg of tiotropium, for example, corresponds to acontent of about 21.7 μg of tiotropium bromide.

Consequently, capsules containing 3 to 10 mg of powder for inhalationpreferably hold between 1.4 and 96.3 μg of tiotropium bromide, accordingto the invention. When the filling is from 4 to 6 mg of inhalable powderper capsule, as is preferred, each capsule contains between 1.9 and 57.8μg, preferably between 3.9 and 46.2 μg, most preferably between 7.7 and28.9 μg of tiotropium bromide. A content of 21.7 μg of tiotropiumbromide, for example, corresponds to a content of about 22.5 μg oftiotropium bromide monohydrate.

Consequently, capsules containing 3 to 10 mg of powder for inhalationpreferably hold between 1.5 and 100 μg of tiotropium bromidemonohydrate. When the filling is from 4 to 6 mg of inhalable powder percapsule, as is preferred, each capsule contains between 2 and 60 μg,preferably between 4 and 48 μg, most preferably between 8 and 30 μg oftiotropium bromide monohydrate.

The Examples which follow describe a possible method of carrying out theprocess according to the invention, taking a powder mixture containingtiotropium bromide monohydrate as the example. The fact that thisprocess described by way of example can be used directly for preparinginhalable powders which contain one or more of the other activesubstances mentioned above will be apparent to anyone skilled in theart. Accordingly, the following Examples serve only to illustrate thepresent invention further without restricting its scope to theembodiments provided hereinafter by way of example.

Starting materials

In the Examples which follow, lactose-monohydrate (200M) is used as thecoarser excipient. It may be obtained, for example, from Messrs DMVInternational, 5460 Veghel/NL under the product name Pharmatose 200M.

In the Examples which follow, lactose-monohydrate (5 μ) is used as thefiner excipient. It may be obtained from lactose-monohydrate 200M byconventional methods (micronising). Lactose-monohydrate 200M may beobtained, for example, from Messrs DMV International, 5460 Veghel/NLunder the product name Pharmatose 200M.

Preparation of tiotropium bromide monohydrate:

15.0 kg of tiotropium bromide, which may be prepared as disclosed in EP418 716 A1, are added to 25.7 kg of water in a suitable reaction vessel.The mixture is heated to 80-90° C. and stirred at constant temperatureuntil a clear solution is formed. Activated charcoal (0.8 kg), moistenedwith water, is suspended in 4.4 kg of water, this mixture is added tothe solution containing the tiotropium bromide and rinsed with 4.3 kg ofwater. The mixture thus obtained is stirred for at least 15 min at80-90° C. and then filtered through a heated filter into an apparatuswhich has been preheated to an outer temperature of 70° C. The filter isrinsed with 8.6 kg of water. The contents of the apparatus are cooled at3-5° C. every 20 minutes to a temperature of 20-25° C. The apparatus isfurther cooled to 10-15° C. using cold water and crystallisation iscompleted by stirring for at least one hour. The crystals are isolatedusing a suction drier, the crystal slurry isolated is washed with 9litres of cold water (10-15° C.) and cold acetone (10-15° C.). Thecrystals obtained are dried in a nitrogen current at 25° C. over 2hours.

Yield: 13.4 kg of tiotropium bromide monohydrate (86% of theory)

The crystalline tiotropium bromide monohydrate thus obtained ismicronised by known methods, to bring the active substance into theaverage particle size which meets the specifications according to theinvention.

For the purposes of the present invention, the average particle size isthe value in μm at which 50% of the particles from the volumedistribution have a particle size which is smaller than or equal to thevalue specified. The laser diffraction/dry dispersal method ofmeasurement is used to determine the total distribution of the particlesize distribution.

The method of determining the average particle size of the variousingredients of the formulation according to the invention is describedas follows.

A) Determining the particle size of finely divided lactose:

Measuring equipment and settings:

The equipment is operated according to the manufacturer's instructions.

Measuring equipment: HELOS Laser-diffraction spectrometer, (SympaTec)Dispersing unit: RODOS dry disperser with suction funnel, (SympaTec)Sample quantity: from 100 mg Product feed: Vibri Vibrating channel,Messrs. Sympatec Frequency of vibrating channel: 40 rising to 100%Duration of sample feed: 1 to 15 sec. (in the case of 100 mg) Focallength: 100 mm (measuring range: 0.9-175 μm) Measuring time: about 15 s(in the case of 100 mg) Cycle time: 20 ms Start/stop at: 1% on channel28 Dispersing gas: compressed air Pressure: 3 bar Vacuum: maximumEvaluation method: HRLDSample preparation/product feed:

At least 100 mg of the test substance are weighed onto a piece of card.Using another piece of card all the larger lumps are broken up. Thepowder is then sprinkled finely over the front half of the vibratingchannel (starting about 1 cm from the front edge). After the start ofthe measurement the frequency of the vibrating channel is varied fromabout 40% up to 100% (towards the end of the measurement). The timetaken to feed in the entire sample is 10 to 15 sec.

B) Determining the particle size of micronised tiotropium bromidemonohydrate:

Measuring equipment and settings:

The equipment is operated according to the manufacturer's instructions.

Measuring equipment: Laser diffraction spectrometer (HELOS), SympatecDispersing unit: RODOS dry disperser with suction funnel, SympatecSample quantity: 50 mg-400 mg Product feed: Vibri Vibrating channel,Messrs. Sympatec Frequency of vibrating channel: 40 rising to 100%Duration of sample feed: 15 to 25 sec. (in the case of 200 mg) Focallength: 100 mm (measuring range: 0.9-175 μm) Measuring time: about 15 s(in the case of 200 mg) Cycle time: 20 ms Start/stop at: 1% on channel28 Dispersing gas: compressed air Pressure: 3 bar Vacuum: maximumEvaluation method: HRLDSample preparation/product feed:

About 200 mg of the test substance are weighed onto a piece of card.Using another piece of card all the larger lumps are broken up. Thepowder is then sprinkled finely over the front half of the vibratingchannel (starting about 1 cm from the front edge). After the start ofthe measurement the frequency of the vibrating channel is varied fromabout 40% up to 100% (towards the end of the measurement). The sampleshould be fed in as continuously as possible. However, the amount ofproduct should not be so great that adequate dispersion cannot beachieved. The time over which the entire sample is fed in is about 15 to25 seconds for 200 mg, for example.

C) Determining the particle size of lactose 200M:

Measuring equipment and settings:

The equipment is operated according to the manufacturer's instructions.

Measuring equipment: Laser diffraction spectrometer (HELOS), SympatecDispersing unit: RODOS dry disperser with suction funnel, SympatecSample quantity: 500 mg Product feed: VIBRI Vibrating channel, Messrs.Sympatec Frequency of vibrating channel: 18 rising to 100% Focal length(1): 200 mm (measuring range: 1.8-350 μm) Focal length (2): 500 mm(measuring range: 4.5-875 μm) Measuring time: 10 s Cycle time: 10 msStart/stop at: 1% on channel 19 Pressure: 3 bar Vacuum: maximumEvaluation method: HRLDSample preparation/product feed:

About 500 mg of the test substance are weighed onto a piece of card.Using another piece of card all the larger lumps are broken up. Thepowder is then transferred into the funnel of the vibrating channel. Agap of 1.2 to 1.4 mm is set between the vibrating channel and funnel.After the start of the measurement the amplitude setting of thevibrating channel is increased from 0 to 40% until a continuous flow ofproduct is obtained. Then it is reduced to an amplitude of about 18%.Towards the end of the measurement the amplitude is increased to 100%.

Apparatus

The following machines and equipment, for example, may be used toprepare the inhalable powders according to the invention:

Forced-action mixer: Diosna, type P100; manufactured by Dierks undSöhne, D-49009 Osnabrück.

Mixing container or powder mixer: Gyrowheel mixer 200 L; type: DFW80N-4;made by: Messrs Engelsmann, D-67059 Ludwigshafen.

Granulating sieve: Quadro Comil; type: 197-S; made by: Messrs Joisten &Kettenbaum, D-51429 Bergisch-Gladbach.

Feed device: KtronSoder; type T20 or T35; made by K-Tron Soder GmbH,D6460 Gelnhausen.

Feed device (for small quantities/especially active substance): Gericke;type GMD60/2; made by Gericke GmbH, D 78239 Rielasingen.

Example 1

Step 1.1 described below for preparing an excipient mixture mayoptionally be omitted. If the desired powder mixture is to contain onlyexcipient of a uniform coarser particle size distribution in addition tothe active substance, the procedure may continue directly according tostep 1.2.

1.1: Excipient mixture:

31.82 kg of lactose monohydrate for inhalation (200M) are used as thecoarser excipient component. 1.68 kg of lactose monohydrate (5 μm) areused as the finer excipient component. In the resulting 33.5 kg ofexcipient mixture the proportion of the finer excipient component is 5%.

About 0.8 to 1.2 kg of lactose monohydrate for inhalation (200M) areadded to a suitable mixing container through a suitable granulatingsieve with a mesh size of 0.5 mm. Then alternate layers of lactosemonohydrate (5 μm) in batches of about 0.05 to 0.07 kg and lactosemonohydrate for inhalation (200M) in batches of 0.8 to 1.2 kg are sievedin. Lactose monohydrate for inhalation (200M) and lactose monohydrate (5μm) are added in 31 and 30 layers, respectively (tolerance: ±6 layers).

The ingredients sieved in are then mixed together with a gravity mixer(mixing at 900 rpm).

1.2: Powder mixture containing active substance:

To prepare the final mixture, 32.87 kg of the excipient mixture (1.1)and 0.13 kg of micronised tiotropium bromide monohydrate are used. Thecontent of active substance in the resulting 33.0 kg of inhalable powderis 0.4%.

32 kg of the excipient mixture obtained according to 1.1 are placed in asuitable forced-action mixer. The forced-action mixer is started up andthe vibrator is switched on. 0.13 kg of micronised tiotropium bromidemonohydrate are metered slowly and continuously into the moving bed ofpowdered excipient by means of a suitable feed device. If necessary, themedicament may also be added through a suitable granulating sieve with amesh size of 0.5 mm. Then the rest of the excipient mixture is fed intothe operating mixer through the feed device and optionally thegranulating sieve. After the ingredients of the mixture have all beenadded, mixing is continued for another 2 minutes. When deposits form onthe walls of the mixer they are scraped off with a plastic spatula. Thenmixing is continued for another 2 minutes.

Example 2

Inhalation capsules (inhalettes) having the following composition wereproduced using the mixture obtained according to Example 1:

tiotropium bromide monohydrate: 0.0225 mg lactose monohydrate (200M):5.2025 mg lactose monohydrate (5 μm): 0.2750 mg hard gelatine capsule:49.0 mg Total: 54.5 mg

Example 3

Inhalation capsules having the composition:

tiotropium bromide monohydrate: 0.0225 mg lactose monohydrate (200M):4.9275 mg lactose monohydrate (5 μm): 0.5500 mg hard gelatine capsule:49.0 mg Total: 54.5 mg

The inhalable powder needed to prepare the capsules was obtainedanalogously to Example 1.

Example 4

Inhalation capsules having the composition:

tiotropium bromide monohydrate: 0.0225 mg lactose monohydrate (200M):5.2025 mg lactose monohydrate (5 μm): 0.2750 mg polyethylene capsule:100.0 mg Total: 105.50 mg

The inhalable powder needed to prepare the capsules was obtainedanalogously to Example 1.

1. A process for preparing a inhalant powder mixture, wherein a firstsubstance having a smaller particle size distribution which comprises abetamimetics, anticholinergics, corticosteroids, dopamine agonists orsalts thereof, is metered continuously through a suitable feed deviceonto a moving bed of a powdered second substance having a largerparticle size distribution.
 2. A process according to claim 1, whereinthe moving bed is mixed using a forced-action mixer.
 3. A processaccording to claim 1, wherein the moving bed is fluidized by means of avibrator.
 4. A process according to claim 1, wherein the components ofthe powder mixture are added to the mixture through a suitable screeningdevice.
 5. A process according to claim 1, wherein the ratio of thefirst substance to the second substance is 1:20.
 6. A process accordingto claim 1, wherein the first substance has an average particle size offrom 0.5 to 10 μm and wherein the second substance has an averageparticle size of from 10 to 100 μm.
 7. A process according to claim 1,wherein the moving bed is mixed using a forced-action mixer and isfluidized by means of a vibrator, the components of the powder mixtureare added to the mixture through a suitable screening device, whereinthe ratio of the first substance and the second substance is 1:20 andwherein the first substance has an average particle size of from 0.5 to10 μm and the second substance has an average particle size of from 10to 100 μm.